Connecting Genes, Brain & Behaviour Flashcards
What two things in animals are positively correlated?
Neural complexity and length of life.
What aren’t feasible with techniques that rely on breeding multiple generations?
Using more complex species as their lifespans are too long for multiple generations.
What are the four steps of forward genetics in animal models?
Mutagenesis, crossing, phenotype, genotype.
What happens in mutagenesis?
Inducing mutations, typically use radiation to induce mutations.
What happens in crossing?
Cross the mutated animal with one of wild-type strain, over generations some offspring will display some mutations and some will display others or not at all.
What happens in phenotype?
Identifying the phenotypes of the offspring.
What happens in genotype?
Finding the associated genotype to the phenotype
What do they look at in forward genetics?
Anatomy, learning and social behaviour
What happens in a reverse genetics approach?
Targeted mutations are introduced and the effect on the phenotype is measured
What is the CRISPR-Cas9 system?
A natural part of a bacterium’s defence against invading viruses
What can the CRISPR-Cas9 be used to do?
Can be used to create targeted genetic mutations in model organisms
What is Cas9?
A nuclease protein (an enzyme that cleaves the chains of nucleotides in nucleic acids into smaller units).
What does guide RNA do to the Cas9 protein?
Guide RNA directs the Cas9 protein to the desired DNA sequence, where the Cas9 cuts the DNA
What can the random repair process do to the gene?
Can disable the gene, or targeted sequences can be introduced to be inserted during repair
What is optogenetics?
Uses microbial opsins to excite or inhibit neurons by light
How do neurons respond to light?
Each responds to light of particular wavelengths
What is the adeno-associated virus (AAV) commonly used to?
Commonly used to introduce the required genetic material, a cell-specific promotor sequence can restrict opsin expression to particular types
What does the channelrhodopsin-2 (ChR2) pump respond to?
Responds to blue light, and allows positive ions into the cell
What does the channelrhodopsin-2 (ChR2) pump response result in?
Depolarisation results in neural excitation
What does halorhodopsin (NpHR) pump respond to?
Responds to yellow light and allows negative ions into the cell
What does the halorhodopsin (NpHR) pump response result in?
Hyperpolarisation results in neuronal inhibition
What is light stimulation delivered through?
Light stimulating a particular rhodopsin is delivered though an implanted optic fibre
What does stimulating ChR2 in mouse amygdala cells do?
Induces a predatory response
What does an optogenetic system in combination with a CRISPR-Cas9 system allow?
Light-controlled protein transcription and light controlled genome editing
What can genetic associations with behaviour do?
Can only hint at the biological pathways involved
What can we do using bioinformatives?
We can ‘translate’ a human genetic mutation to target a homologous gene in a model organism
What do model organisms allow?
More direct measurement at multiple levels; structure, function, behaviour
What is the HTR1A?
It is the human gene encoding the serotonin-1A receptor
What can imaging genetics do?
Connects genes, brain anatomy, brain function and behaviour
Where is the SNPrs6295 located?
In the promotor region of HTR1A
What is the SNPrs6295 associated with?
Trait anxiety
How is the SNPrs6295 associated with trait anxiety?
Individuals with one or two copies of the G allele showed lower trait anxiety than individuals homozygous for the C allele
What is the SNPrs6295 also associated with?
Serotonin-binding potential
How is the SNPrs6295 associated with serotonin-binding potential?
Additional copies of the G allele were associated with increased binding potential
What does the G allele do?
Impairs the transcriptional repression of the promotor, causes increased expression of the 5-HT1A receptor
How was binding potential measured with PET?
Detects radiation from an injected tracer with a high affinity for 5-HT1A receptors
What did binding potential measured with PET find?
Higher density of receptors leads to higher binding potential
What is the 5-HT1A receptor?
It is an autoreceptor
Why is 5-HT1A an autoreceptor?
It is located at the presynaptic membrane, where it binds neurotransmitters released by the neuron. This is a key part of the system for regulating neurotransmitter release
What is reduced capacity for regulation of 5-HT associated with?
Increased amygdala reactivity
What was capacity for regulation of 5-HT release the same as?
Same as the PET measure of 5-HT1A binding potential
What is increased amygdala reactivity associated with?
Increased trait anxiety
What does lower levels of the SNPrs6295 G allele lead to?
Low 5-HT binding potential, high amygdala reactivity, high trait anxiety
What does higher levels of the SNPrs6295 G allele lead to?
High 5-HT binding potential, low amygdala reactivity, low trait anxiety
What is the HTR1A SNP associated with?
Amygdala reactivity, additional copies of the G allele were associated with decreased reactivity
What is increased serotonin-binding potential throughout the brain associated with?
Lower anxiety
What is this convergent evidence of?
Presence of the G allele of rs6295 impairs repression of HTR1A transcription, leads to increased receptor density, indexed by binding potential, in turn leads to decreased amygdala reactivity, finally predisposes to low anxiety
What happens conversely?
Absence of the G allele of rs6295 promotes repression of HTR1A transcription, leads to decreased receptor density, indexed by binding potential, leads to increased amygdala reactivity, predisposes to high anxiety
By comparing measurements across multiple levels what can we reveal?
The likely biological pathway linking a genetic variant to a behavioural phenotype
